The Art of Scientific Research: New Tunable Expression Tools for Bacteroides in the Gut Microbiota

Fig. 1: The colorful confetti in the top half of the image represents different types of bacteria in the genus Bacteroides. The magenta is the mucus of the intestinal lining, as well as plant material ingested by the mouse, and at the bottom, the larger blue circles are the mouse cells that make up the intestinal lining.[1]

The image to the left is of the colon of a dead lab mouse, though it wouldn’t look out of place on the walls of a hip art museum. The photo was made possible by a new technology to study bacteria called “tunable expression tools” developed by researchers Weston Whitaker and Liz Stanley in the Sonnenburg Lab at Stanford. It has the potential to dramatically change the landscape for gut microbiota research and someday play into diagnostics and treatments across the medical field.[1]

Research into the human gut microbiota, or the collection of bacteria that inhabit the human colon, has grown from a largely unknown phenomenon to the topic of many news articles, books and TED Talks. It’s now known that the gut microbiota is intimately connected to human health—affecting weight gain and loss, the development of the immune system, and even the functioning of the brain. To read more on this, check out this article.

Bacteria of the Bacteroides genus are the most abundant kind found in the human gut for those who eat a Westernized diet, comprising a full 60% of the trillion bacteria that reside there.[1] In the image, each different species can be seen as a different color under the microscope. Sure, this makes for a pretty picture, but more importantly it gives scientists a new way to learn about the bacteria that inhabit us. In the paper where this image was published, researchers used it and pictures like it to directly view where bacteria live within the gut. This enabled the discovery of a previously unknown method used by some bacterial species to exclude competitors introduced into their environment. Essentially, bacteria that are already established are able to prevent new bacteria that are introduced from colonizing the gut long term.[1] This is mediated by control of a particular niche environment in the gut, called crypts.

Crypts are small crevices between the villi (small finger like projections that aid in nutrient absorption) of the intestinal wall bacteria. For reasons that are not yet fully understood, crypt colonization plays a major role in a bacteria’s ability to exclude competitors while persisting itself. A firm understanding of this process could form the foundation for discovering ways to have commensal bacteria within the gut exclude pathogenic bacteria, like E. coli or Salmonella. In theory, capitalizing on this process could help prevent harmful bacteria from reaching a high enough level to cause disease.

Fig. 2: Along the x-axis are different promoters, each with its own characteristic level of expression. On the y-axis is the level of expression, measured as luminescence when the promoters are used for fluorescent proteins. As you can see, the promoters range over several orders of magnitude.[1]

Furthermore, the tunable expression tools that Whitaker and Shepherd et. al developed can be applied to more than just the color of the bacteria. It can fine tune the expression of many genes inserted into Bacteroides. Technology for modifying and inserting genes in Bacteroides has existed for a while, but the traditional method had only limited control of the expression of the new genes. For example, a scientist could add a gene for the production of GFP, a protein that glows, into a bacteria’s DNA, only to discover that bacteria didn’t make use of the new genetic material and produced too little GFP to make a difference. Genetic material is essentially a blueprint, just because a cell knows how to make a product doesn’t necessarily mean that it will. For that, you’d also need to control the factors that influence how much and when each gene is converted into functional protein. With Whitaker and Shepherd’s tunable expression tools, expression can be controlled extremely precisely over several orders of magnitude.[1]

Finally, one of the biggest differences between the old and new technologies is how long they take. Previously, only a few bacterial strains could be modified at a time and the process took about a week.[1] Testing out a hundred or so different modifications to find the right one could take months. The new tools allow the process to be completed in less than half the time—about three days. More importantly, the tool can create nearly a hundred new mutants at a time. Practically, this is an enormous gain for researchers, as engineering bacteria is a part of a large variety of research projects, and has been fundamental to advances as varied as the mass production of insulin for diabetics to growing corn that produces its own pesticides.

Furthering genome engineering technologies for bacteria could increase the speed of scientific progress and discoveries. Already researchers are looking into the possibility that bacteria in our gut could be engineered to detect when we’re getting sick, before we’re even aware of it, and let us know or react appropriately. If bacteria living within us may one day produce our medicines for us, this ability to finely tune the variety and amount of medicine they produce is extremely important.

Research that describes the development of new technologies is often less glamorous than research that discovers a new truth about the world. However, itis high impact; these new techniques can be implemented by labs around the world, providing a backbone for many of the new discoveries we’ll see in the future.

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